ABSTRACT
Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration1,2, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo3-5, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca2+ spiking is controlled directly by water through these hypo-osmosensors-that is, Ca2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins6. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca2+-permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.
Subject(s)
Arabidopsis , Calcium Signaling , Calcium , Germination , Osmolar Concentration , Pollen , Arabidopsis/metabolism , Arabidopsis/genetics , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Calcium/metabolism , Calcium Channels/genetics , Calcium Channels/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Germination/genetics , Mutation , Pollen/genetics , Pollen/metabolism , Water/metabolism , HEK293 Cells , Humans , DehydrationABSTRACT
Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues1-4. H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca2+ increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.
Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/enzymology , Hydrogen Peroxide/metabolism , Membrane Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Arabidopsis/genetics , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/genetics , Calcium/metabolism , Calcium Channels/metabolism , Calcium Signaling , Cysteine/chemistry , Cysteine/metabolism , Enzyme Activation , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mutation , Oxidation-Reduction , Plant Cells/metabolism , Protein Domains , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/geneticsABSTRACT
Salinity is detrimental to plant growth, crop production and food security worldwide. Excess salt triggers increases in cytosolic Ca2+ concentration, which activate Ca2+-binding proteins and upregulate the Na+/H+ antiporter in order to remove Na+. Salt-induced increases in Ca2+ have long been thought to be involved in the detection of salt stress, but the molecular components of the sensing machinery remain unknown. Here, using Ca2+-imaging-based forward genetic screens, we isolated the Arabidopsis thaliana mutant monocation-induced [Ca2+]i increases 1 (moca1), and identified MOCA1 as a glucuronosyltransferase for glycosyl inositol phosphorylceramide (GIPC) sphingolipids in the plasma membrane. MOCA1 is required for salt-induced depolarization of the cell-surface potential, Ca2+ spikes and waves, Na+/H+ antiporter activation, and regulation of growth. Na+ binds to GIPCs to gate Ca2+ influx channels. This salt-sensing mechanism might imply that plasma-membrane lipids are involved in adaption to various environmental salt levels, and could be used to improve salt resistance in crops.
Subject(s)
Arabidopsis/cytology , Arabidopsis/metabolism , Calcium Signaling , Calcium/metabolism , Glycosphingolipids/metabolism , Plant Cells/metabolism , Sodium Chloride/metabolism , Arabidopsis/genetics , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Membrane Potentials/drug effects , Mutation , Salt Stress/genetics , Salt Stress/physiology , Sodium Chloride/pharmacology , Sodium-Hydrogen Exchangers/metabolismABSTRACT
Plants have evolved diverse strategies to accommodate saline environments. More insights into the knowledge of salt stress regulatory pathways will benefit crop breeding. RADICAL-INDUCED CELL DEATH 1 (RCD1) was previously identified as an essential player in salt stress response. However, the underlying mechanism remains elusive. Here, we unraveled that Arabidopsis NAC domain-containing protein 17 (ANAC017) acts downstream of RCD1 in salt stress response, and its ER-to-nucleus transport is triggered by high salinity. Genetic and biochemical evidence showed that RCD1 interacts with transmembrane motif-truncated ANAC017 in the nucleus and represses its transcriptional activity. Transcriptome analysis revealed that genes associated with oxidation reduction process and response to salt stress are similarly dysregulated in loss-of-function rcd1 and gain-of-function anac017-2 mutants. In addition, we found that ANAC017 plays a negative role in salt stress response by impairing the superoxide dismutase (SOD) enzyme activity. Taken together, our study uncovered that RCD1 promotes salt stress response and maintains ROS homeostasis by inhibiting ANAC017 activity.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Stress, Physiological/genetics , Plant Breeding , Salt Tolerance/genetics , Cell Death , Gene Expression Regulation, Plant , Plants, Genetically Modified/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Transcription Factors/metabolismABSTRACT
The flagellin epitope flg22, a pathogen-associated molecular pattern (PAMP), binds to the receptor-like kinase FLAGELLIN SENSING2 (FLS2), and triggers Ca2+ influx across the plasma membrane (PM). The flg22-induced increases in cytosolic Ca2+ concentration ([Ca2+ ]i ) (FICA) play a crucial role in plant innate immunity. It's well established that the receptor FLS2 and reactive oxygen species (ROS) burst undergo sensitivity adaptation after flg22 stimulation, referred to as desensitization and resensitization, to prevent over responses to pathogens. However, whether FICA also mount adaptation mechanisms to ensure appropriate and efficient responses against pathogens remains poorly understood. Here, we analysed systematically [Ca2+ ]i increases upon two successive flg22 treatments, recorded and characterized rapid desensitization but slow resensitization of FICA in Arabidopsis thaliana. Pharmacological analyses showed that the rapid desensitization might be synergistically regulated by ligand-induced FLS2 endocytosis as well as the PM depolarization. The resensitization of FICA might require de novo FLS2 protein synthesis. FICA resensitization appeared significantly slower than FLS2 protein recovery, suggesting additional regulatory mechanisms of other components, such as flg22-related Ca2+ permeable channels. Taken together, we have carefully defined the FICA sensitivity adaptation, which will facilitate further molecular and genetic dissection of the Ca2+ -mediated adaptive mechanisms in PAMP-triggered immunity.
Subject(s)
Arabidopsis Proteins/genetics , Arabidopsis/genetics , Calcium/metabolism , Endocytosis/genetics , Gene Expression Regulation, Plant , Protein Kinases/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Ligands , Protein Kinases/metabolismABSTRACT
Potassium (Kâº) is an essential macronutrient of living cells and is the most abundant cation in the cytosol. K⺠plays a role in several physiological processes that support plant growth and development. However, soil K⺠availability is very low and variable, which leads to severe reductions in plant growth and yield. Various K⺠shortage-activated signaling cascades exist. Among these, calcium signaling is the most important signaling system within plant cells. This review is focused on the possible roles of calcium signaling in plant responses to low-K⺠stress. In plants, intracellular calcium levels are first altered in response to K⺠deficiency, resulting in calcium signatures that exhibit temporal and spatial features. In addition, calcium channels located within the root epidermis and root hair zone can then be activated by hyperpolarization of plasma membrane (PM) in response to low-K⺠stress. Afterward, calcium sensors, including calmodulin (CaM), CaM-like protein (CML), calcium-dependent protein kinase (CDPK), and calcineurin B-like protein (CBL), can act in the sensing of K⺠deprivation. In particular, the important components regarding CBL/CBL-interacting protein kinase (CBL/CIPK) complexes-involved in plant responses to K⺠deficiency are also discussed.
Subject(s)
Arabidopsis/metabolism , Calcium Channels/metabolism , Calcium Signaling , Calcium/metabolism , Gene Expression Regulation, Plant , Potassium/metabolism , Arabidopsis/drug effects , Arabidopsis/genetics , Arabidopsis/growth & development , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Calcium Channels/genetics , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Calmodulin/genetics , Calmodulin/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Gene Expression Regulation, Developmental , Plant Roots/drug effects , Plant Roots/metabolism , Potassium/pharmacology , Potassium Deficiency , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Soil , Stress, PhysiologicalABSTRACT
Fungal immunomodulatory protein (FIP)-sch2, an immunomodulatory protein identified in the ascomycete Stachybotrys chlorohalonata by a sequence similarity search, is a novel member of the FIP family. FIP-sch2 shares high sequence identity, structure, and evolutionary conservation with previously reported FIPs. It was satisfactorily expressed in Escherichia coli with a glutathione S-transferase (GST) tag and purified by GST-affinity magnetic beads. To characterize the direct antitumor effects, human lung adenocarcinoma A549 cells were treated with different concentrations of recombinant FIP (rFIP)-sch2 in vitro, and the results showed that rFIP-sch2 could reduce cell viability dose-dependently with a half-maximal inhibitory concentration (IC50) of 9.48 µg/mL. Furthermore, rFIP-sch2 at 8 µg/mL could significantly induce apoptosis and interrupt migration in A549 cells. Notably, the antitumor effect of rFIP-sch2 was equivalent to that of rLZ-8 but was obviously increased compared to rFIP-fve. In addition, the exploration of the antitumor mechanism suggested that rFIP-sch2 induced lung cancer cell death by activating apoptosis and inhibiting migration. Our results indicated that rFIP-sch2 was a promising candidate for use in future cancer therapy.
Subject(s)
Cell Movement/drug effects , Cell Proliferation/drug effects , Fungal Proteins/pharmacology , Immunomodulation , Lung Neoplasms/pathology , Stachybotrys/chemistry , A549 Cells , Apoptosis/drug effects , Cell Survival/drug effects , Escherichia coli/genetics , Fungal Proteins/genetics , Fungal Proteins/isolation & purification , Glutathione Transferase/genetics , Humans , Real-Time Polymerase Chain Reaction , Recombinant Proteins/isolation & purification , Recombinant Proteins/pharmacology , Sequence Alignment , Stachybotrys/genetics , Stachybotrys/isolation & purificationABSTRACT
It is well established that both salt and reactive oxygen species (ROS) stresses are able to increase the concentration of cytosolic free Ca(2+) ([Ca(2+)]i), which is caused by the flux of calcium (Ca(2+)). However, the differences between these two processes are largely unknown. Here, we introduced recombinant aequorin into rice (Oryza sativa) and examined the change in [Ca(2+)]i in response to salt and ROS stresses. The transgenic rice harbouring aequorin showed strong luminescence in roots when treated with exogenous Ca(2+). Considering the histological differences in roots between rice and Arabidopsis, we reappraised the discharging solution, and suggested that the percentage of ethanol should be 25%. Different concentrations of NaCl induced immediate [Ca(2+)]i spikes with the same durations and phases. In contrast, H2O2 induced delayed [Ca(2+)]i spikes with different peaks according to the concentrations of H2O2. According to the Ca(2+) inhibitor research, we also showed that the sources of Ca(2+) induced by NaCl and H2O2 are different. Furthermore, we evaluated the contribution of [Ca(2+)]i responses in the NaCl- and H2O2-induced gene expressions respectively, and present a Ca(2+)- and H2O2-mediated molecular signalling model for the initial response to NaCl in rice.
Subject(s)
Calcium Signaling , Gene Expression Regulation, Plant , Oryza/metabolism , Reactive Oxygen Species/metabolism , Sodium Chloride/metabolism , Aequorin/analysis , Aequorin/metabolism , Apoproteins/analysis , Apoproteins/metabolism , Oryza/genetics , Plant Proteins/analysis , Plant Proteins/metabolism , Plant Roots/genetics , Plant Roots/metabolism , Plants, Genetically Modified/metabolism , Recombinant Proteins/analysis , Recombinant Proteins/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, affecting millions of people worldwide. Due to the lack of systemic radiation therapy in hepatocellular carcinoma, researchers have been investigating the use of yttrium-90 (90Y) radioembolization for local-regional tumor control since the 1960s. With the development of glass and resin 90Y microspheres and the durable local control, good long-term efficacy, and equivalent tumor responsiveness and tolerability of 90Y-selective internal irradiation compared with alternative therapies such as transarterial chemoembolization (TACE) and sorafenib, 90Y radioembolization has gradually been applied in the treatment of hepatocellular carcinoma of all stages. In this article, we summarize the latest progress of 90Y in the treatment of hepatocellular carcinoma in terms of its principle, advantages, indications, contraindications, efficacy and adverse effects.
ABSTRACT
As sessile organisms, plants cannot survive in harmful environments, such as those characterized by drought, flood, heat, cold, nutrient deficiency, and salt or toxic metal stress. These stressors impair plant growth and development, leading to decreased crop productivity. To induce an appropriate response to abiotic stresses, plants must sense the pertinent stressor at an early stage to initiate precise signal transduction. Here, we provide an overview of recent progress in our understanding of the molecular mechanisms underlying plant abiotic stress sensing. Numerous biomolecules have been found to participate in the process of abiotic stress sensing and function as abiotic stress sensors in plants. Based on their molecular structure, these biomolecules can be divided into four groups: Ca2+-permeable channels, receptor-like kinases (RLKs), sphingolipids, and other proteins. This improved knowledge can be used to identify key molecular targets for engineering stress-resilient crops in the field.
ABSTRACT
Sorafenib (SF) is a first-line drug for the treatment of hepatocellular carcinoma (HCC) in clinical practice. However, acquired drug resistance tremendously limits the clinical efficacy of sorafenib in treating HCC, which has attracted great attention. PDL1 plays a crucial role in the drug resistance of HCC. Here, a codelivery system based on poly-SS-lysine modified chitosan (TAT-C-SS-P) was established and was applied to deliver sorafenib and PDL1-siRNA for synergetic HCC therapy. The successful synthesis of TAT-C-SS-P was confirmed by 1H NMR. Additionally, sorafenib and PDL1-siRNA were successfully transported into the cells as the decreased expression of VEGF and PD-L1 by administrated with TAT-C-SS-P@SF@ PDL1-siRNA. Simultaneously, the expression of pro-apoptosis proteins cyt-c and Bax was prominently augmented, whereas the expression of anti-apoptosis protein Bcl-2 was decreased. The reduced expression of PDL1 resulted in the downregulation of P-GP and MRP1, which contributed to more sorafenib aggregation in tumor cells. Moreover, TAT-C-SS-P@PDL1-siRNA@SF efficiently promotes apoptosis of HepG2-SI cells, as the apoptosis rate rised to 73 %. A sorafenib-insensitive model was established to evaluate in vivo antitumor effect of TAT-C-SS-P@PDL1-siRNA@SF. TAT-C-SS-P@PDL1-siRNA@SF showed a tumor inhibition rate of 90.2 ± 3.5 % and no significant decrease in body weight. Taken together, our study provided compelling evidence that TAT-C-SS-P@PDL1-siRNA@SF has great potential application in the treatment of HCC clinically.
Subject(s)
Carcinoma, Hepatocellular , Chitosan , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Sorafenib/pharmacology , Chitosan/pharmacology , Lysine/pharmacology , RNA, Small Interfering , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , B7-H1 Antigen , Cell Line, Tumor , Apoptosis , Drug Resistance, Neoplasm/genetics , Cell ProliferationABSTRACT
For antibacterial purposes, a photothermal and photodynamic antibacterial membrane was prepared through electrospinning. We used zein as the substrate and introduced Protoporphyrin IX (PpIX) into the protein structure. Then, we used electrospinning technology to weave the modified zein into a fiber structure. We finally introduced a metallic polyphenol network (MPN) coating on the fiber surface to form the final membrane: MPN@Zein-PpIX. Then, we investigated the photothermal and photodynamic properties of the membrane and assessed its antibacterial activity with in vitro agar plate counting methods. The MPN@Zein-PpIX membrane exhibited good singlet oxygen generation and excellent photothermal conversion. Additionally, it showed good antibacterial capacity in vitro, owing to the combination of photothermal and photodynamic properties. Our research provides a simple approach to prepare a multifunctional membrane with excellent antibacterial ability. We used the electrospinning technique to anchor PpIX onto zein to produce a fiber membrane (Zein-PpIX) that can be adhered in situ to improve the biocompatibility of PpIX, and the MPN makes the membrane surface more hydrophilic and more accessible to adhere to biological tissues. The MPN@Zein-PpIX membrane provided new ideas for combining PDT and PTT, and it had great potential for use in the antibacterial application field.
ABSTRACT
Pro-inflammatory M1 macrophages possess the ability to change the immunosuppressive tumor microenvironment by releasing various inflammatory factors simultaneously, which can effectively inhibit tumor progression and relapse. Promoting macrophage polarization towards M1 may be an effective way to treat Melanoma. However, the risk of cytokine storm caused by the proliferation and excessive activation of M1 macrophages greatly limits it as a biosafety therapeutic strategy in anti-tumor immunotherapy. Therefore, how to engineer natural M1 macrophage to a biocompatible biomaterial that maintains the duration time of tumor suppressive property duration time still remains a huge challenge. To achieve this goal, we developed an injectable macroporous hydrogel (M1LMHA) using natural M1 macrophage lysates and alginate as raw materials. M1LMHA had excellent biocompatibility, adjustable degradation rate and could sustainably release varieties of natural inflammatory factors, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), etc. M1LMHA could repolarize anti-inflammatory M2 macrophages to M1 macrophages by the synergistic effect of released tiny inflammatory factors via the NF-κB pathway. This study supported that M1LMHA might be an effective and safe tool to activate tumor-associated immune cells, improving the efficiency of anti-tumor immunotherapy.
Subject(s)
Alginates , Hydrogels , Tumor-Associated Macrophages , Alginates/chemistry , Alginates/pharmacology , Mice , Animals , Hydrogels/chemistry , Hydrogels/pharmacology , Tumor-Associated Macrophages/drug effects , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Melanoma/therapy , Melanoma/immunology , Melanoma/drug therapy , Melanoma/pathology , Porosity , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , RAW 264.7 Cells , Cytokines/metabolism , Cell Line, Tumor , Tumor Microenvironment/drug effectsABSTRACT
Strain Tibet-S9a3(T) was isolated from Qinghai-Tibet Plateau permafrost, China. The isolate was a Gram-negative, non-motile, non-spore-forming short rod. The 16S rRNA gene sequence indicated that strain Tibet-S9a3(T) was a member of the genus Paracoccus and was closely related to Paracoccus aestuarii B7(T) (98.2â% 16S rRNA gene sequence similarity), 'P. beibuensis' JLT1284 (97.9â%), P. homiensis DD-R11(T) (97.4â%), P. zeaxanthinifaciens ATCC 21588(T) (97.4â%) and other type strains of the genus (93.7-96.7â%). The G+C content of the genomic DNA was 69.1 mol% and the major isoprenoid quinone was ubiquinone-10. The major fatty acids were C18â:â1ω7c (87.6â%), C18â:â0 (4.3â%) and C10â:â0 3-OH (2.0â%). DNA-DNA relatedness between strain Tibet-S9a3(T) and P. aestuarii B7(T) was 37.9â%. On the basis of phenotypic and genotypic characteristics, it is suggested that strain Tibet-S9a3(T) represents a novel species of the genus Paracoccus, for which the name Paracoccus tibetensis sp. nov. is proposed. The type strain is Tibet-S9a3(T) (â=âCGMCC 1.8925(T) â=âNBRC 105667(T)).
Subject(s)
Paracoccus/classification , Phylogeny , Soil Microbiology , Bacterial Typing Techniques , Base Composition , China , DNA, Bacterial/genetics , Fatty Acids/analysis , Molecular Sequence Data , Nucleic Acid Hybridization , Paracoccus/genetics , Paracoccus/isolation & purification , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Ubiquinone/analysisABSTRACT
Liver cancer is highly malignant, has a low sensitivity to chemotherapy, and is associated with poor patient prognosis. The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). For over 10 years, before the discovery of lenvatinib, sorafenib was only first-line therapeutic agent available for the treatment of advanced HCC. However, several clinical studies have shown that a considerable proportion liver cancer patients are insensitive to sorafenib. Very few patients actually substantially benefit from treatment with sorafenib, and the overall efficacy of the drug has not been satisfactory; therefore, sorafenib has attracted considerable research attention. This study, which is based on previous studies and reports, reviews the potential mechanisms underlying sorafenib resistance and summarizes combination therapies and potential drugs that can be used to sensitize HCC cells to sorafenib.
ABSTRACT
The critical challenges in repairing oral soft and hard tissue defects are infection control and the recovery of functions. Compared to conventional tissue regeneration methods, nano-bioactive materials have become the optimal materials with excellent physicochemical properties and biocompatibility. Dental-derived mesenchymal stem cells (DMSCs) are a particular type of mesenchymal stromal cells (MSCs) with great potential in tissue regeneration and differentiation. This paper presents a review of the application of various nano-bioactive materials for the induction of differentiation of DMSCs in oral and maxillofacial restorations in recent years, outlining the characteristics of DMSCs, detailing the biological regulatory effects of various nano-materials on stem cells and summarizing the material-induced differentiation of DMSCs into multiple types of tissue-induced regeneration strategies. Nanomaterials are different and complementary to each other. These studies are helpful for the development of new nanoscientific research technology and the clinical transformation of tissue reconstruction technology and provide a theoretical basis for the application of nanomaterial-modified dental implants. We extensively searched for papers related to tissue engineering bioactive constructs based on MSCs and nanomaterials in the databases of PubMed, Medline, and Google Scholar, using keywords such as "mesenchymal stem cells", "nanotechnology", "biomaterials", "dentistry" and "tissue regeneration". From 2013 to 2023, we selected approximately 150 articles that align with our philosophy.
ABSTRACT
Plants are exposed to various environmental stresses. The sensing of environmental cues and the transduction of stress signals into intracellular signaling are initial events in the cellular signaling network. As a second messenger, Ca2+ links environmental stimuli to different biological processes, such as growth, physiology, and sensing of and response to stress. An increase in intracellular calcium concentrations ([Ca2+]i) is a common event in most stress-induced signal transduction pathways. In recent years, significant progress has been made in research related to the early events of stress signaling in plants, particularly in the identification of primary stress sensors. This review highlights current advances that are beginning to elucidate the mechanisms by which abiotic environmental cues are sensed via Ca2+ signals. Additionally, this review discusses important questions about the integration of the sensing of multiple stress conditions and subsequent signaling responses that need to be addressed in the future.
ABSTRACT
Background: Angiogenic tissue engineering is a vital problem waiting to be settled for periodontal regeneration. Erythropoietin, a multieffect cytokine, has been reported as a protective factor for cell fate. According to our previous study, erythropoietin has a significantly angiogenic effect on periodontal ligament stem cells. To further explore its potential effects and mechanism, we studied biological behaviors of periodontal ligament stem cells under inflammatory microenvironment induced by different concentrations (0, 10, 20, 50, and 100 ng/mL) of tumor necrosis factor-α (TNF-α) and examined how different concentrations (0, 5, 10, 20, and 50 IU/mL) of erythropoietin changed biological behaviors of periodontal ligament stem cells. Materials and Methods: Cell Counting Kit-8 was used for cell proliferation assay. Annexin V-PI-FITC was used for cell apoptosis through flow cytometry. Matrigel plug was adopted to measure the angiogenic capacity in vitro. RNA sequencing was used to detect the downstream signaling pathway. Quantitative real-time polymerase chain reaction was conducted to examine mRNA expression level. Western blot and immunofluorescence were applied to testify the protein expression level. Results: Periodontal ligament stem cells upregulated apoptosis and suppressed autophagy and angiogenesis under inflammatory microenvironment. Erythropoietin could activate autophagy to rescue apoptosis and angiogenesis levels of periodontal ligament stem cells through the Akt/Erk1/2/BAD signaling pathway under inflammatory microenvironment. Conclusions: Erythropoietin could protect periodontal ligament stem cells from inflammatory microenvironment, which provided a novel theory for periodontal regeneration.
ABSTRACT
PURPOSE: Bladder carcinoma (BLCA) is the most common urinary tract malignancy and exhibits a poor response to chemotherapy. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in a wide variety of regulatory cellular processes, including apoptosis and the DNA-damage response (DDR). LB100, a small molecule inhibitor of PP2A, has been shown to act as a chemo-sensitizer in multiple types of cancer. However, the anti-tumor effect and mode of action of LB100 in BLCA have yet to be identified. METHODS: In vitro and in vivo experiments were performed to assess the anti-tumor effect of LB100 alone or in combination with gemcitabine. Mass spectrometry (MS)-based phosphoproteomics analysis was used to identify the downstream substrates of PP2A and to explore the mechanism underlying LB100-induced DNA damage and apoptosis. In addition, we established a chemo-resistant BLCA cell line (RT-112-R) by prolonged drug exposure and determined the effect of LB100 in enhancing genotoxicity in BLCA cell lines and xenograft mouse models. RESULTS: We found that LB100 is sufficient to induce an anti-tumor response in BLCA cells by inducing DNA damage and apoptosis both in vitro and in vivo. Furthermore, we found that PP2A potentially dephosphorylates p-p21-ser130 to stabilize p21. Inhibition of PP2A by LB100 increased the level of p-p21-ser130, subsequently leading to a reduction in p21 level in a dose-dependent manner. In addition, we found that treatment of LB100 abrogated the G1/S cell cycle checkpoint, resulting in increased phosphorylation of γH2AX in BLCA cells. Moreover, LB100 enhanced genotoxicity in chemo-resistant BLCA cells by inducing DNA damage and apoptosis in vitro and in vivo. CONCLUSION: Our findings indicate that PP2A may serve as a potential therapeutic target in BLCA through regulating p21 stability.
Subject(s)
Protein Phosphatase 2 , Urinary Bladder Neoplasms , Animals , Humans , Mice , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Protein Phosphatase 2/antagonists & inhibitors , Protein Phosphatase 2/metabolism , Urinary Bladder/metabolism , Urinary Bladder Neoplasms/drug therapy , Xenograft Model Antitumor AssaysABSTRACT
Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.